Clara Lenherr explores the newly discovered human-specific characteristics of neurons and discusses how the uniqueness of human neurons brings into question what we already know about human cognition.
The ability of neurons to carry out complex computations when integrating the thousands of inputs that they receive is thought to be the basis of cognition. The two main factors that influence the ability of neurons to integrate inputs and carry out specific functions are their physical structure and biochemical composition. Specifically, the biochemical composition of neurons refers to the nature of their neurotransmitters and membrane channels or receptors. A recent study published in Nature showed that the biophysical properties of a subpopulation of neurons in the cerebral cortex, the brain’s outer layer of neural tissue, are conserved relative to size across several mammalian species. This means that larger mammals with larger neurons are able to conduct more current. Notably, human neurons did not follow this pattern and were found to conduct substantially less current than expected for their size. The results of the study call into question whether our advanced cognitive abilities as humans are down to how our neurons uniquely process information.
The study of neuroscience is largely aimed at understanding the basis of human cognitive abilities and the mechanisms underlying human-specific neurodegenerative and psychiatric disorders. Yet, the vast majority of neuroscience research is carried out on animal models, mainly rodents, because of the technical difficulties and ethical considerations of experimenting on humans. A key consideration in evaluating the findings of animal research is therefore the extent to which human brains differ from other species. It has been suggested that human neurons are more efficient at transmitting information than their monkey counterparts, whereas monkey neurons produce more robust responses. While robustness ensures fast and reliable behavioural responses to threats, efficiency can improve information capacity and thereby enhance cognition. To determine the biological substrates for basic (robust) versus advanced (efficient) cognition, it is necessary to study species-differences at the level of individual neurons, while also taking into account how the characteristics of an organism change as a function of size.
Studying the electrical behaviour of human neurons has been one of the greatest challenges in the field of neuroscience. Recording the electrical activity of individual neurons requires live human brain tissue, which is extremely difficult to obtain since it can only rarely be extracted from epilepsy patients undergoing surgical removal of a small brain region. The first direct measurements of electrical activity from human neocortical neurons have only recently been reported. In 2018, a paper published by a team at MIT showed that a subtype of human cortical excitatory neurons are less excitable than their rodent counterparts. In addition, human cortical excitatory neurons exhibit more local electrical activity that does not contribute to their overall firing, in the region that receives most inputs. This means that human cortical excitatory neurons may carry out more complex local transformations of incoming inputs than their counterparts in rodents. Contrastingly, another paper published by a team at Humboldt-Universität in Berlin showed that another subtype of human cortical neurons are more excitable than their rodent counterparts. Thus, different neuronal subpopulations may have distinct species-divergent properties. Moreover, human neurons have been shown to uniquely be capable of implementing the “exclusive OR” operation, a computation that enables the amplification of weak rather than strong inputs. The presence of human-specific electrical activity underlying a unique computation that has not been demonstrated ever before in neurons calls into question what other computational capabilities exist.
A new paper published by the same MIT group in November 2021 compared the biophysical properties of cortical neurons across 10 mammalian species, including rodents, ferrets, rabbits, monkeys, and humans. They found a size-dependent rule whereby larger neurons exhibit an increased capacity for ion movement across the membrane, known as ionic conductance, which underlies current flow. Overall, this ensures a constant conductance per unit brain area: larger neurons have a lower surface area-to-volume ratio so the total surface area for a specific brain area is lower, but the increased membrane conductance overcomes this size-dependent effect. Notably, however, human neurons showed an average ionic conductance four times lower than expected. In support of this, human neurons were found to contain fewer ion channels of two specific subtypes that play prominent roles in determining thresholds for electrical events to occur.
Since conductance determines how greatly incoming inputs influence neuronal output, and given the significantly lower ionic conductance found in human neurons, it is likely that input-output processing differs between humans and other mammals. The full significance of this finding has yet to be elucidated. Interestingly, ionic conductance is related to the amount of energy used up by neurons. The reduction in humans may therefore enable more energy to be allocated to other mechanisms that make neuronal activity more efficient. Perhaps the differences in conductance per brain volume underlies the ability of human neurons to prioritise efficiency over robustness, as described earlier.
Although these studies look promising and have resulted in meaningful conclusions, they are not without limitations. The main limitation of the above study is that human brain tissue was acquired from patients with medically intractable epilepsy who have undergone resective surgery. However, the researchers emphasised an ability to overcome this limitation by ensuring the extracted tissue displayed no known abnormalities in MRI scans prior to the procedure and by carrying out standard neuropathologic assessment of the brain tissue prior to electrical recordings. Significantly, they found no difference in the biophysical properties of neurons in rats where epilepsy had been induced compared to normal rats. Nevertheless, this limitation should be taken into consideration when evaluating the credibility of findings and emphasises the need to develop better methods for studying human neurons.
We are only just beginning to understand how evolution has shaped the biophysical properties of neurons across species. The implications of understanding the evolution of neuronal biophysics extend beyond understanding the basis of our cognitive abilities. The findings may also hint at what underlies our susceptibility to psychiatric and neurodegenerative disorders. Moreover, uniquely human properties may partially explain why several therapies derived from animal models are ineffective for treating humans. This study, among others, has proved that understanding neuronal biophysics is a promising starting point for understanding what makes us human.
This article was written by Clara Lenherr and edited by Natasha Kisseroudis
Clara Lenherr is a Neuroscience Master’s student pursuing research on the mechanisms of neural plasticity and computation that underlie learning and memory. Find her on Twitter @Lenherr_C.